Mutant Isocitrate Dehydrogenase 1 Alters Extracellular Vesicle Secretion and Cargo Composition in Cellular Models

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

Abstract excerpt

Somatic mutations in isocitrate dehydrogenase 1 (IDH1) define major subtypes of adult diffuse gliomas and occur across a broad spectrum of cancers. These mutations ablate the conventional turnover of isocitrate to alpha-ketoglutarate and confer the neomorphic production of D-2-hydroxyglutarate (D2HG), which drives epigenetic remodeling. Growing evidence suggests this neomorphic activity may also affect how tumor cells communicate; small extracellular vesicles (sEVs) are elevated in gliomas, though how mutant IDH1 shapes sEV production and cargo remains poorly understood. Using glioblastoma and chondrosarcoma cell models, we show expression of mutant IDH1 correlates with a trend of increased sEV secretion, and that D2HG is packaged into sEVs that are taken up by cells. Cell-permeable D2HG treatment dose-dependently increased sEV release from IDH1 wild type cells. Untargeted proteomics showed that mutant IDH1 expression remodeled sEV cargo in a cell type-specific fashion, with mutant chondrosarcoma sEVs enriched in one-carbon metabolism enzymes, and mutant glioma sEVs in lysosomal luminal proteins and endoplasmic reticulum (ER) chaperones. Mutant IDH1 glioma cell transcriptomics suggested expanded ER folding capacity and reduced ribosomal pathways, and sEVs from these cells decreased nascent protein synthesis in IDH1 wild type recipient cells. Together, this suggests sEVs can serve as carriers of mutant IDH1 phenotypes.